Serum asymmetric dimethylarginine and arginine levels predict microvascular and macrovascular complications in type 2 diabetes mellitus.

BACKGROUND: Increased oxidative stress in diabetes increases nitric oxide (NO) oxidation and low l-arginine (Arg) could further reduce NO and impair vascular function, thereby accelerating, in the long run, vascular complications. We therefore measured Arg and asymmetric dimethylarginine (ADMA) levels in patients with type 2 diabetes mellitus (T2DM) and healthy controls. Additionally, we observed the diabetic individuals over time to see if Arg and asymmetric dimethylarginine predicted T2DM complications. METHODS: We examined baseline serum Arg and ADMA levels in a cohort of 105 participants with type 2 diabetes and compared them with an age- and weight-matched nondiabetic group of 137 individuals who served as a reference population. Additionally, we assessed whether Arg and/or ADMA predicted macrovascular and microvascular complications over 6 years of follow-up. RESULTS: Serum Arg was lower in individuals with T2DM than in controls (64 ± 28 vs 75 ± 31 µmol/L; P = .009) and inversely related to hemoglobin A1c (r = -0.2; P = .002). Over follow-up, we observed that participants with T2DM in the lowest quartile of Arg had increased risk for the subsequent evolution of nephropathy, peripheral neuropathy, and composite microvascular complications (odds ratio [OR] = 5.5; 95% confidence interval [CI] -1.9 to 16; P = .002). The highest ADMA quartile was associated with increased risk for both microvascular (OR = 4.5; 95% CI -1.4 to 14.1; P = .009) and 6.5-year incident macrovascular complications (OR = 8.3; 95% CI 1.9-35.5; P = .004). CONCLUSION: l-Arginine levels are lower in individuals with T2DM than in matched controls. Both low Arg and high ADMA, independent of each other and adjusted for classical risk factors, predict the incidence of microvascular complications.

KISS1 receptor is preferentially expressed in clinically non-functioning pituitary tumors.

OBJECTIVE: KISS1 is a metastasis suppressor gene involved in cancer biology. Given the high expression levels of KISS1 and KISS1R in the hypothalamus and the pituitary respectively, we hypothesized that this system could possibly affect tumor invasiveness and clinical behavior of pituitary tumors. METHODS: Expression levels of KISS1 and KISS1R mRNA were evaluated by RT-PCR. Clinical information pertaining tumor characteristics was extracted from patients' charts. RESULTS: Tumors from 39 patients (21 females, mean age 47.5 years) were examined. KISS1R was expressed in 26 (67%) of samples (94% of NFPA, 42% of GH-, 67% of ACTH-, and 25% of PRL-secreting adenomas) and was found more often in female patients (81 vs. 50% males, p < 0.05); and in NFPA (94 vs. 45.5% in secreting tumors; p = 0.003). Patients expressing KISS1R were older at presentation (50.5 ± 1.4 vs. 38.1 ± 1.3 years; p = 0.008). In the multivariate analysis, factors significantly associated with KISS1R expression included female gender (OR 13.8, 95 % CI 1.22-155.9; p = 0.03) and having a NFPA (OR 24.7, 95% CI 1.50-406.4; p = 0.02). Tumor size, invasiveness and age at presentation were not independently associated with KISS1R expression. Pituitary tumors and normal pituitary were negative for KISS1 mRNA expression. CONCLUSIONS: The majority of human NFPA expressed KISS1R with lower rates of expression in other types of pituitary tumors. KISS1R expression did not impart a clinical beneficial tumor phenotype, as it was not associated with tumor size or invasiveness. Additional studies are required to elucidate the role of KISS1 receptor in pituitary gland physiology and pathology.

Alcohol Drinks Induce Acute Lowering in Circulating l-Arginine in Obese and Type 2 Diabetic Subjects.

Since low serum l-arginine (Arg) and high asymmetric dimethylarginine (ADMA) can predict microvascular complications in type 2 diabetes mellitus (T2DM), we tested whether Arg and ADMA are affected by diet and physical activity in overweight/obese and T2DM subjects. We tested the effects on serum Arg and ADMA of single loads of dextrose, protein, fat, or alcohol (∼300 calories each); one episode of physical exercise; and 12 weeks of standard lifestyle modification (dietary and physical activity counseling). Alcohol drink was followed by ∼30% lowering in Arg. Arg and ADMA increased after a protein load but remained stable after glucose or fat load or 30 min of treadmill walk. Following 12 weeks of lifestyle modification, ADMA declined only in subjects achieving weight loss >5%. In conclusion, alcohol is a previously unrecognized acute suppressor of serum Arg. Lifestyle modification lowers ADMA in subjects who achieve weight loss >5%. Clinical Trial Registration Number: NCT04406402.

Multidisciplinary Treatment of the Metabolic Syndrome Lowers Blood Pressure Variability Independent of Blood Pressure Control.

Blood pressure (BP) variability (BPV) contributes to target organ damage independent of BP. The authors examined the effect of a 1-year multidisciplinary intervention on BPV in patients with the metabolic syndrome (MetS) as defined by criteria from the Third Report of the Adult Treatment Panel. Forty-four nondiabetic patients underwent clinical and biochemical profiling, 24-hour ambulatory BP monitoring (ABPM), body composition, carotid intima-media thickness, and carotid-femoral pulse wave velocity (PWV). The intervention targeted all MetS components. BPV was assessed by the standard deviation of daytime systolic BP derived from ABPM. Patients with low and high BPV (lower or higher than the median daytime standard deviation of 11.6 mm Hg) did not differ in regards to systolic and diastolic BP, age, fasting glucose, glycated hemoglobin, and body mass index, but the high-variability group had higher values of low-density lipoprotein and leg fat. The 1-year intervention resulted in weight reduction but not BP-lowering. BPV declined in the high-variability group in association with lowering of PWV, C-reactive protein, glycated hemoglobin, alanine aminotransferase, asymmetric dimethylarginine, and increased high-density lipoprotein cholesterol. A multidisciplinary intervention independent of BP-lowering normalized BPV, lowered PWV, and enhanced metabolic control.